The present Invention relates to catalytic asymmetric hydrogenation of olefins to synthesize chiral alpha-amino phosphonates and selected novel chiral alpha-amino phosphonates. The chiral alpha-amino phosphonates are either useful as biocides, antibiotics and/or useful in the preparation of phosphorous-containing analogs of peptides, i.e., phosphoric peptides or pseudopeptides having known uses. For example, such phosphorus-type compounds have been shown to be effective as antibiotics, antibiotic enhancers, or enzyme Inhibitors.
In the past desired stereoisomers have been difficult to obtain. Laborious and expensive processes such as those using fractional crystallization and recycle loops have been common in procedures involving a resolution step to obtain a desired stereoisomer. More recently some olefins have been subjected to asymmetric hydrogenation over rhodium and other metal coordination catalysts having optically active ligands.
Such asymmetric hydrogenation for the preparation of selected enantiomers is shown by the following references:
U.S. Pat. No. 4,939,288; PA1 U.S. Pat. No. 4,277,420; PA1 U.S. Pat. No. 4,912,221; PA1 EP Application No. 90307750.1; PA1 U.S. Pat. No. 4,906,773; PA1 U.S. Pat. No. 4,916,252; PA1 U.S. Pat. No. 4,316,847; PA1 EP Application No. 89403599.7; PA1 Schollkoph et al, Liebigs Ann. Chem., 1985, 555-559; PA1 Aboujaoude et al, Phosphorus Sulfur, 1983, 18(1-2-3), pp. 133-6; PA1 Bissane et al, Pept. 1990 Proc. Eur. Pept. Symp. 21st, Meeting Date 1990, pp. 438-9, PA1 Glowak et al, Khim. Primen. Fosfororg, Soedin., Tr. Yubileinol Kong., 6th Meeting Date 1977, 1981, pp.2251-3; PA1 Ornstein, J. Org. Chem., 1989, 54(9), pp. 2251-2; PA1 Sauveur et al, Phosphorus Sulfur, 1983, 14(3), pp.341-6; PA1 Growiak and Sawka-Dobrowolska, Tetrahedron Letters, 1977, No. 45, pp. 3965-8; and PA1 Parsons et al, J. Med. Chem. 1988, No. 31, pp. 1772-8. PA1 Kukhar and Sclodenko, Russ. Chem. Rev., 1987, pp. 1504-32; and PA1 Dhawan and Redmore, Phosphorus and Sulfur, 1987, 32, pp. 119-44. PA1 Sawamura et al, Tetrahedron Letters, 1989, Vol. 30, No. 17, pp 2247-50; PA1 Sting and Steglich, Synthesis, 1990, February, pp. 132-4; PA1 Solodenko et al, Tetrahedron, 1991, Vol. 47, No. 24, pp. 3989-98; PA1 Kafarski and Lejczak, Can. J. Chem. 1983, 61, pp. 2425-30; PA1 Atherton et al, Antimicrobial Agents and Chemotherapy, 1979, May, pp. 877-83; PA1 Atherton et at, J. Med. Chem., 1986, 29, pp. 29-40; PA1 Scholkoph and Schutze, Liebigs Ann. Chem., 1987, pp. 45-9; PA1 Bartlett and Lamden, Bioorganic Chemistry, 1986, 14, pp. 356-77; PA1 Huber and Vasella, Helvetica Chimica Acta, 1987, 70, pp. 1461-76. PA1 (2) alkyl of from one to six carbons substituted by one or two hydroxyl, chloro, or fluoro; PA1 (3) phenyl substituted by one to three substituent(s) consisting of PA1 (4) tolyl; PA1 (5) tolyl substituted by one to three substituents consisting of PA1 (6) naphthyl optionally attached through a CH.sub.2 group and optionally substituted by one to three substituents consisting of PA1 (7) indol-3-yl, indol-2-yl, or imidazol-4-yl, or indol-3-ylmethyl, indol-2-ylmethyl or imidazol-4-ylmethyl; PA1 (8) NHA wherein A is PA1 (9) R.sub.12 (R.sub.13 R.sub.14 C).sub.m V wherein V is 0 or NH and R.sub.12, R.sub.13 and R.sub.14 are independently as defined above; PA1 (10) N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above; PA1 (11) NR.sub.15 NR.sub.16 wherein R.sub.15 and R.sub.16 are joined to form a 4 to 6 membered saturated nitrogen containing heterocycle which is (i) azetidinyl, (ii) pyrrolidinyl, (iii) piperidinyl, or (iv) morpholinyl; PA1 (12) R.sub.17 OCH.sub.2 O wherein R.sub.17 is PA1 (13) R.sub.17 OCH.sub.2 CH.sub.2 OCH.sub.2 wherein R.sub.7 is independently as defined above; PA1 (14) alkynyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above; PA1 (15) alkenyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above; PA1 (2) alkyl of from 1 to 6 carbons optionally substituted by one or two hydroxyl, chloro or fluoro; PA1 (3) cycloalkyl of from 3 to 7 ring carbons; PA1 (4) ar.sub.4 which is a group such as phenyl, or phenyl substituted by one to three substituent(s) consisting of PA1 (5) ar.sub.5 which is a group such as tolyl; PA1 (6) ar.sub.6 which is a group such as tolyl substituted by one to three substituents consisting of PA1 (7) ar.sub.7 which is a group optionally attached through a CH.sub.2 and is naphthyl or naphthyl substituted by one to three substituents consisting of PA1 (8) ar.sub.8 which is a group such as indol-3-yl, indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or imidazol-4-ylmethyl (preferably unsubstituted or substituted phenyl or indol-3-yl); PA1 (9) NHA wherein A is PA1 (10) R.sub.12 (R.sub.13 R.sub.14 C).sub.m V wherein V is 0 or NH and R.sub.12, R.sub.13 and R.sub.14 are independently as defined above; PA1 (11) N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above; PA1 (12) NR.sub.15 NR.sub.16 wherein R.sub.15 and R.sub.16 are joined to form a 4 to 6 membered saturated nitrogen containing heterocycle which is (i) azetidinyl, (ii) pyrrolidinyl, (iii) piperidinyl, or (iv) morpholinyl; PA1 (13) R.sub.17 OCH.sub.2 O wherein R.sub.17 is PA1 (14) R.sub.17 OCH.sub.2 CH.sub.2 OCH.sub.2 wherein R.sub.17 is independently as defined above; PA1 (15) alkynyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above; PA1 (16) alkenyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above;
East German Application Nos. 280,527; 280,528; 280,529; 240,372 described in corresponding Derwent Abstract Numbers 90-362220/49, 90-362221/49, 90-362222/49, 87-057083/09, respectively;
Int. J. Peptide Protein Res. 41, 1988, 269-280;
Japanese Number 3002152A described in WPI Acc No. 91-048825;
German Appl. No. 140-036 described in Derwent Abstract No. 34661C/20.
Some (1-Aminoalkyl)phosphonic acids, the phosphonic acid analogs of amino acids, and particularly the selected enantioselective synthesis of optically pure aminophosphonic acids and phosphonopeptides have been prepared by resolution and by asymmetric synthesis using chiral auxiliaries. This is exemplified by the following references:
Schollkoph et al report that "attempts to hydrogenate 3a" (which is N-[1-(dimethoxyphosphoryl)ethenyl]formamide) at room temperature, normal pressure) in the presence of (R,R)-DIPAMP failed." Schollkoph et al disclose the reduction of certain dehydro alpha-amino phosphonates by catalytic asymmetric hydrogenation in the presence of rhodium (+) DIOP catalyst. Thus, surprisingly, both the chemical yield and the asymmetric induction providing enantiomeric enhancements (ee) of the present invention process provide essentially pure compounds of a particular stereoisomeric form including selected chiral compounds new essentially pure not previously known. Further, Genet et al, Tetrahedron letters, 1986, Vol. 27, No. 38, pp 4573-76, provide comparisons of DIOP and DIPAMP in a different asymmetric allylation consistent with Schollkoph.
Reported diastereomeric mixtures of 1-aminoalkylphosphono type compounds are found in numerous references of which the following are examples:
Baylis et al, J. Chem. Soc. Perkin Trans I 1984., 1984,2845-53;
Yuan and Qi, Synthesis, 1988, June, 472-4 disclose 1-amino-substituted benzyl phosphonic acids where the benzyl includes various substituents.
U.S. Pat. No. 4,016,148 discloses peptide derivatives having a moiety characterized by the replacement of the carboxyl group of a naturally occurring L alpha-amino acid by a phosphorus group including a --P(O)(OH).sub.2 group.
Recent reviews disclosing the preparation of selected diastereomeric and chiral alpha-amino phosphonates are found in the following references respectively:
The following additional references disclose various specific chiral alpha-amino phosphonates:
The interesting biological properties of .alpha.-aminophosphonates make them attractive analogues of .alpha.-aminoacids, [(a) Redmore, D. Top. Phosphorus Chem., 1976, 8, 515; (b) Petrov, K. A.; Chauzov, V. A.; Erokhina, T. S. Russ. Chem. Rev. 1974, 43, 984; (c) Kafarski, P.; Mastarlerz, P. Aminophosphonates: Natural Occurance, Biochemistry and Biological Properties, Bertrage zur Wirkstofforschung, Ak. Ind. Kompl. DDR, 1984, 21.] While they resemble their carbon counterparts, the tetrahedral phosphorus also allows them to function as transition state analogues. These pharmaceutically-interesting compounds [Certain phosphorus analogues of .alpha.-amino phosphonates are being investigated by the pharmaceutical industry as antibiotics, see; (a) Atherton, F. R.; Hall, M. J.; Hassall, C. H.; Lambert, R. W.; Llod, W. J.; Ringrose, P. S. Antimicrob. Agents Chemother., 1979, 15, 696; (b) Chakravarty, P. K.; Greenlee, W. J.; Parsons, N. H.; Patchett, A. A.; Combs, P.; Roth, A.; Busch, R. D.; Mellin, T. N. J. Med. Chem., 1989, 32, 1886 and references therein.] have been synthesized by various racemic routes, but the need to develop a practical asymmetric method still exists. The present invention now successfully fulfills this need.
.alpha.-Amino phosphonates have recently been reported to serve as starting materials for the preparation of potent inhibitors of HIV-1 protease. (Dreyer, G. B. New diamino phosphinic acid derivatives are aspartic protease inhibitors used to treat viral infections especially HIV type 1. Patent Application W09900954-A1, Jan. 22, 1992, assigned to SmithKline Beecham Corp.) This application is incorporated herein by reference to provide the basis for utility for the present invention process and its intermediates. Since the .alpha.-amino phosphonate employed by Dreyer et al was racemic (Dreyer, G. B.; Choi, J. K.; Meek, T. D.; Tomaszek, T. A., Jr. 203rd American Chemical Society Meeting, San Francisco, Calif. Apr. 5-10, 1992, Medicinal Chemistry #179), the inhibitor was made as a mixture of isomers necessitating a tedious chromatographic separation in order to isolate the most active constituent. The most active isomer was derived from the phosphorus analogue of phenylalanine with the L(R) absolute configuration. Not only would the methodology described herein be adaptable to the preparation of the most active isomer of the SKB HIV-protease inhibitor, but to a wide variety of analogues as well. Intermediates of U.S. Pat. No. 4,946,833 and each of European Application Nos. 89401595.7 and 90402226.6 are related to the novel compound I of the present invention. German Application 4029444A abstracted in Derwent Abstract No. 91-095191/14 discloses compounds for regulating plant growth related to the novel compounds of Formula II of the present invention. Further, EP 207,890A disclosed in Derwent Abstract No. 87-001565/01 includes 1-amino-2-phenylethylphosphorus acid derivatives as microbiocidal and biocidal agents.
The flexibility of the present synthesis permits the synthesis of very unique analogues of .alpha.-amino phosphonates that are related to known compounds having biological properties relative to molecules available by more demanding syntheses. The literature is replete with examples of novel amino acid side chains designed to impart improved biological properties to analogous molecules.